Pre-clinical Development of the Oligomer Modulator anle138b and Establishment of a Novel Seeding-based Biomarker

Promising Outcomes of Original Grant:
In our previous work, we assessed the therapeutic potential of the oligomer modulator anle138b in pre-clinical models of Parkinson’s disease (PD). Anle138b inhibits the formation of small aggregates (called oligomers) of the protein alpha-synuclein, which researchers believe may be toxic to nerve cells. Based on the efficacy seen in these pre-clinical models, we now want to take the next steps to move anle138b to clinical trials in humans.

Objectives for Supplemental Investigation:           
Based on the results of our previous grant, we will address four tasks:

• First, we want to finalize development of formulations for long-term oral application of anle138b in humans that provides optimal bioavailability.
• The second task comprises the long-term toxicity testing of anle138b in pre-clinical models required before the start of clinical trials.
• Third, in order to establish a therapeutic window to guide future clinical development, we will perform a dose-response relationship (pharmacokinetics/pharmacodynamics) study of anle138b in two disease-relevant models. Data about the minimal effective dose from these studies combined with the results of the toxicity study are crucial to calculate a safe starting dose for the first-in-human study.
• A fourth task aims to establish a novel method that allows detection of aggregated alpha-synuclein protein based on its ability to induce further protein aggregation for early diagnosis of Parkinson’s disease (PD) as well as for monitoring disease progression in clinical trials.

Importance of This Research for the Development of a New PD Therapy:
Clinical trials with novel therapeutic compounds require intense pre-clinical assessment to achieve best therapeutic effects with a minimum risk of adverse effects. This project will address these aspects by determining toxicological properties of anle138b as well as the best therapeutic dose. Moreover, our work will result in a formulation that is suitable for long-term administration in humans. Finally, the development of a new diagnostic tool for the reliable and sensitive detection of pathological alpha-synuclein aggregates enables a better identification of patients suited for therapeutic trials and provides a direct molecular readout for drugs inhibiting alpha-synuclein pathology. Thus, this project could significantly speed the development of a cure for PD.